Elucidation of the coordination of metal ions to Aβ is essential to understand their role in its aggregation and to rationally design new chelators with potential therapeutic applications in Alzheimer disease. Because of that, in the last 10 years several studies have focused their attention in determining the coordination properties of Cu 2+ interacting with Aβ. However, more important than characterizing the first coordination sphere of the metal is the determination of the whole Cu 2+-Aβ structure. In this study, we combine homology modeling (HM) techniques with quantum mechanics based approaches (QM) to determine plausible three-dimensional models for Cu 2+-Aβ(1-16) with three histidines in their coordination sphere. We considered both ε and δ coordination of histidines 6, 13, and 14 as well as the coordination of different possible candidates containing oxygen as fourth ligand (Asp1, Glu3, Asp7, Glu11, and CO Ala2). Among the 32 models that enclose COO -, the lowest energy structures correspond to [O E3,N δH6,N εH13,N εH14] (1), [O E3,N δH6,N δH13,N δH14] (2), and [O D7,N εH6,N δH13,N δH14] (3). The most stable model containing CO Ala2 as fourth ligand in the Cu 2+ coordination sphere is [O cA2,N εH6,N δH13,N εH14] (4). An estimation of the relative stability between Glu3 (1) and CO Ala2 (4) coordinated complexes seems to indicate that the preference for the latter coordination may be due to solvent effects. The present results also show the relationship between the peptidic and metallic moieties in defining the overall geometry of the complex and illustrate that the final stability of the complexes results from a balance between the metal coordination site and amyloid folding upon complexation. © 2011 American Chemical Society.